Summary of Work: Our group is interested in understanding the role of the Intersectin adaptor protein in regulating signal transduction cascades in general and receptor tyrosine kinases (RTKs) in particular. Intersectin is a member of a growing family of adaptor proteins that possess conserved Eps15 homology (EH) domains as well as additional protein recognition motifs. EH-containing proteins play an integral role in regulating clathrin-dependent endocytosis. Intersectin consists of two NH4-terminal EH domains, a coiled-coil region and 5 tandem Src homology 3 (SH3) domains. A variety of experiments have implicated Intersectin in the regulation of endocytosis. However, several lines of evidence suggested to us that Intersectin might also function in regulation or activation of signal transduction pathways. Using transient transcriptional reporter assays, we have demonstrated that Intersectin activates the Elk-1 transcription factor and cooperates with growth factors such as epidermal growth factor to synergistically activate Elk-1. Although Elk-1 is a major transcriptional target of the MAPK pathway, we have demonstrated that Intersectin activation of Elk-1 is MAPK-independent. In further support of the notion that Intersectin activates signaling pathways, we have shown that Intersectin expression induces oncogenic transformation of rodent fibroblasts and accelerates progesterone induced maturation of X. laevis oocytes suggesting that Intersectin may link endocytosis with regulation of cell growth and differentiation. Our current focus is on understanding the mechanism of Intersectin activation of Elk-1 and the importance of this activity for Intersectin function. In addition, given its role in regulation of endocytosis, we are currently examining the possible function of Intersectin in modulating RTK function through regulation of RTK endocytosis, recycling and degradation.